Michael Hageman

School of Pharmacy - Pharmaceutical Chemistry
Distinguished Professor
Distinguished Professor
Ph.D.
Primary office:
785-864-8199
Multidisciplinary Research Building
Room 160
University of Kansas
2095 Constant Ave.
Lawrence, Kansas 66047


Summary
Professor Hageman earned his B.S. in Pharmacy and Ph.D. in Pharmaceutical Chemistry from the University of Kansas. His research experiences have included industrial positions in R&D at Pharmacia, Pfizer and Bristol-Myers Squibb. See more detail below.

Summary of Scientific Experiences
Prior to joining the Department of Pharmaceutical Chemistry at The University of Kansas as a Distinguished Professor in 2017, I spent 30+ years working in the Pharmaceutical Industry. I have extensive experience in physicochemical characterization and preclinical assessment of new chemical entities (NCE), including proteins, peptides, oligonucleotides, protein drug conjugates, prodrugs, and other small molecule based therapeutics. I have been directly involved in the Discovery process with chemical lead selection, chemical lead optimization, and drug candidate selection for transition into clinical development. Those preclinical experiences include drug delivery research for both parenteral and oral dosage form design, with particular emphasis on designing specialized formulation strategies to overcome poor drug stability and poor aqueous solubility, with the ultimate goal of enhancing developability and commercialization. I have extensive experience, and resulting patents, on the generation of solublilzed dosage forms for administration, parenteral and oral, of both immediate release and controlled release dosage forms. Similarly, critical experience in factors which influence processing technologies, such as lyophilization and spray drying for both biologics and small molecule NCE, provides a window to later phase manufacturing challenges. In depth lab work utilizes a materials characterization approach to understand the fundamental role of both physicochemical and physicomechanical properties in both the chemical and physical stability within these amorphous systems, which dictate the resulting bioperformance of these systems. I have expertise at understanding the role of polymers and excipients in both the dissolution behaviour of these solid dispersion systems and their ability to produce and maintain supersaturated drug concentrations to enhance oral absorption. My background in industrial R&D, my experience in physical analysis, formulation screening, and developability assessment of numerous different drug modalities, will all provide me the background necessary to support the practical delivery aspects of this project in a way which has a line-of-sight to clinical evaluation and a potential product..

Education

Ph.D., Pharmaceutical Chemistry, University of Kansas

M.S., Pharmaceutical Chemistry, University of Kansas

B.S., Pharmacy, University of Kansas

Research

Physical Pharmacy & Drug Delivery Research Laboratory – Michael J. Hageman, Ph.D.
With 30+ years of experience in industry, my academic pursuits focus on a research program that is driven by problem statements of interest from both industrial and academic colleagues. The labs will focus on Physical Pharmacy and Drug Delivery (P2D2) as it relates to understanding physicochemical properties of the drug that dictate formulation and process design. The problem statements are pursued in a highly collaborative manner with both industrial and academic colleagues. The P2D2 Labs will have the capability to produce, process, and characterize small molecule, peptide, protein and cellular-based therapeutics as formulated and stabilized through amorphous- based formulations to be delivered orally and parenterally.


I. Apply processing capabilities based on mini-lab scale spray-drying and lyophilization to generate amorphous materials for investigation, characterization and application to problem statement resolution.

  1. Control dissolution behavior and modulate bioperformance of amorphous solid dispersions (ASD) and coprecipitates. Examine the ability to enhance oral absorption or normalize a drug’s molecular physicochemical properties through generation of amorphous drug formulated in solid dispersions.
  2.  Describe ASD dissolution through the fundamental properties of water penetration, swelling, polymer dissolution, disentanglement, phase separation, new phase formation, colloidal particle generation and drug migration. Determine the impact of ASD drug/excipient composition, dosage form design attributes, and dissolution media composition.

II. Apply mini-lab scale fluidized-bed coating, coupled with drug solubilization strategies (prodrugs, lipids, cyclodextrins, micellar) and/or amorphous solid dispersions (ASDs) for modulated release of drugs requiring enhanced solubilization strategies, from a spray-layered multi-particulate bead platform.

  1.  Design drug delivery and dosage form strategies with solubilized drugs and ASDs to modify biopharmaceutics via manipulation of Cmax to Cmin ratios without sacrificing overall enhanced exposure being targeted with these technologies; this is especially focused on formulation design for high dose toxicology studies in preclinical species.
  2.  Couple drug solubilization strategies and ASD with targeted local drug delivery to the lower GI tract and mesenteric lymph. The focus will be for localized, not systemic, treatment of infectious bowel disease (IBD) and tumors with extensive mesenteric lymph bed involvement.

III. Identify mechanisms of, and mitigation strategies for, instability of peptide and protein drugs in lyophilized and spray-dried solids during processing, storage and residence at the site of administration.

  1.  Develop highly hydrated solids as high concentration solution models to study peptide / protein stability during dehydration, rehydration, and dissolution/diffusion steps.
  2.  Develop models to study the role of formulation composition and design on peptide / protein stability and release (dissolution/diffusion) from drug-depots at 37°C, hence influencing subcutaneous release and subsequent lymphatic or capillary absorption.

IV. Examine processing, stabilization, formulation and delivery of live cells such as CAR-T cells parenterally and microbiota-derived cells orally.

  1.  Move beyond cryobiology and cryopreservation to explore stabilization of cells through “reduced hydration” via lyophilization, evaporative-drying, spray-drying, and spray-layering on beads for parenteral / oral delivery, exploring process parameters and storage stabilization.
  2.  Establish analytical methods to ascertain stability and changes in cell based properties as manifested in cell viability, growth and specific cellular functional attributes.

With 30+ years of experience in industry, my academic pursuits focus on a research program that is driven by problem statements of interest from both industrial and academic colleagues. The labs will focus on Physical Pharmacy and Drug Delivery (P2D2) as it relates to understanding physicochemical properties of the drug that dictate formulation and process design. The problem statements are pursued in a highly collaborative manner with both industrial and academic colleagues. The P2D2 Labs will have the capability to produce, process, and characterize small molecule, peptide, protein and cellular-based therapeutics as formulated and stabilized through amorphous- based formulations to be delivered orally and parenterally.

I. Apply processing capabilities based on mini-lab scale spray-drying and lyophilization to generate amorphous materials for investigation, characterization and application to problem statement resolution.
  1. Control dissolution behavior and modulate bioperformance of amorphous solid dispersions (ASD) and coprecipitates. Examine the ability to enhance oral absorption or normalize a drug’s molecular physicochemical properties through generation of amorphous drug formulated in solid dispersions.
  2.  Describe ASD dissolution through the fundamental properties of water penetration, swelling, polymer dissolution, disentanglement, phase separation, new phase formation, colloidal particle generation and drug migration. Determine the impact of ASD drug/excipient composition, dosage form design attributes, and dissolution media composition.
II. Apply mini-lab scale fluidized-bed coating, coupled with drug solubilization strategies (prodrugs, lipids, cyclodextrins, micellar) and/or amorphous solid dispersions (ASDs) for modulated release of drugs requiring enhanced solubilization strategies, from a spray-layered multi-particulate bead platform.
  1.  Design drug delivery and dosage form strategies with solubilized drugs and ASDs to modify biopharmaceutics via manipulation of Cmax to Cmin ratios without sacrificing overall enhanced exposure being targeted with these technologies; this is especially focused on formulation design for high dose toxicology studies in preclinical species.
  2.  Couple drug solubilization strategies and ASD with targeted local drug delivery to the lower GI tract and mesenteric lymph. The focus will be for localized, not systemic, treatment of infectious bowel disease (IBD) and tumors with extensive mesenteric lymph bed involvement.

III. Identify mechanisms of, and mitigation strategies for, instability of peptide and protein drugs in lyophilized and spray-dried solids during processing, storage and residence at the site of administration.

  1.  Develop highly hydrated solids as high concentration solution models to study peptide / protein stability during dehydration, rehydration, and dissolution/diffusion steps.
  2.  Develop models to study the role of formulation composition and design on peptide / protein stability and release (dissolution/diffusion) from drug-depots at 37°C, hence influencing subcutaneous release and subsequent lymphatic or capillary absorption.

IV. Examine processing, stabilization, formulation and delivery of live cells such as CAR-T cells parenterally and microbiota-derived cells orally.

  1.  Move beyond cryobiology and cryopreservation to explore stabilization of cells through “reduced hydration” via lyophilization, evaporative-drying, spray-drying, and spray-layering on beads for parenteral / oral delivery, exploring process parameters and storage stabilization.
  2.  Establish analytical methods to ascertain stability and changes in cell based properties as manifested in cell viability, growth and specific cellular functional attributes
Scientific Contributions Summary

1. Improved formulation and drug delivery of peptides: This research area is aimed at improving the delivery of peptides molecules by understanding the physicochemical properties of the drug and subsequent drug stability modification through formulation. In particular, the role of variables such as viscosity, cosolvents, surfactants, lipids and polymers in liquid formulations, on both stability and release from the injection site, are examined and modulated. In solid lyophilized peptide formulations, the impact of water on the plasticization of the amorphous glassy systems, and enhanced drug mobility within those systems, is determined and contrasted to increased chemical reactivity of water. Prolonged delivery of polypeptides (eg. growth releasing factor), as described in the patent, are evidence of taking this knowledge to the implementation stage for an injectable product.

a.  Li R, Hageman MJ, Topp EM. Effect of Viscosity on the Deamidation Rate of a Model ASN-Hexapeptide. J Peptide Res. 59, 211-220 (2002).
b.  Foster TP, Moseley WM, Caputo JF, Hageman MJ. Aqueous Prolonged Release Parenteral Formulation. (for a polypeptide) Granted as U.S. Patent 6,429,195 on August 6, 2002.
c.  Lai MC, Hageman MJ, Schowen RL, Borchardt RT, Laird BB, Topp EM. Chemical Stability of Peptides in Polymers. II. Discriminating Between Solvent and Plasticizing Effects of Water on Peptide Deamidation in Poly(vinyl pyrrolidone). J Pharm Sci. 88, 1081-1089 (1999).
d.  Lai MC, Hageman MJ, Schowen RL, Borchardt RT, Topp EM. Chemical Stability of Peptides in Polymers. I. Effect of Water on Peptide Deamidation in Poly(vinyl alcohol) and Poly(vinyl pyrrolidone) Matrices. J Pharm Sci. 88, 1073-1080 (1999).
 
2. Drug delivery and stability of proteins with emphasis on moisture in lyophilized proteins: This research area is focused on understanding and improving formulation and processing variables for the stability of proteins as is relevant to drug delivery and long term storage. The role of moisture, both as a plasticizer of the formulation or as a chemical reactant itself, is explored extensively and applied to formulate and stabilize lyophilized proteins. The characterization of instability and subsequent strategies for the mitigation thereof, require careful characterization of both chemical and physical decomposition pathways for the proteins, with particular attention to aggregation and interactions of the protein with the components of formulation or overall delivery system. Through such as understanding, aqueous prolonged release formulations of proteins, as demonstrated in the patent, can be developed.

a.  Hageman MJ, Possert ML. Aqueous Prolonged Release Formulation", (for a protein) Granted U.S. Patent 6,699,490 on March 2, 2004.
b.  Miller BL, Hageman MJ, Thamann TJ, Barròn LB, Schöneich C. Solid State Photodegradation of Bovine Somatotropin (Bovine Growth Hormone): Evidence for Tryptophan-mediated Photo-oxidation of Disulfide Bonds. J Pharm Sci. 92(8), 1698-1709 (2003).
c.  Sarciaux JM, Hageman MJ. Effects of Bovine Somatotropin (rbSt) Concentration at Different Moisture Levels on the Physical Stability of Sucrose in Freeze-Dried rbSt/Sucrose Mixtures. J Pharm Sci. 86, 365-371 (1997).
d.  Bell LN, Hageman MJ, Bauer JM. Impact of Moisture on Thermally Induced Denaturation and Decomposition of Lyophilized Bovine Somatotropin. Biopolymers. 35, 201-209 (1995).

3. Facilitate oral drug absorption via enhanced dissolution of solid dispersions and generation of supersatured solutions: The bioperformance of amorphous solid dispersions are highly dictated by the physicochemical properties of the drug, the properties of the polymers used, and the media to which they are being delivered. The dissolution of the solid dispersion is also impacted by the
effective surface area provided through the dosage form and the rate at which the polymer excipients themselves can dissolve. Similarly, the rate of subsequent drug precipitation, and hence supersaturation, is also impacted by the excipients, the drug, constituents of the dissolution media and the complex nature in which they interact with one another. This research aims to dissect and understand these phenomena at a fundamental level so that drug delivery can be optimized and developable or patented formulations can be generated.
 
a.  Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, Hussain M, Haskell R, Stefanski K, Qian F. Sodium Lauryl Sulphate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole / HPMC-AS Amorphous Solid Dispersion. Mol Pharm. 13(8):2787-95 (2016).
b.  Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, Hussain M, Haskell R, Stefanski K, Qian F. Initial drug release from amorphous solid dispersions controlled by polymer release and drug-polymer interaction. Pharm Res. 33(10):2445-58 (2016).
c.  Vickery RD, Stefanski KJ, Su CC, Hageman MJ, Vig BS, Betigeri S, Bioavailable Compositions of Amorphous Piperidinyl Compounds, Granted as Patent US 9,095,585 on August 4, 2015.
d.  Chen XQ, Stefanski K, Shen H, Huang C, Caporuscio C, Yang W, Lam P, Su C, Gudmundsson O, Hageman M. Oral Delivery of Highly Lipophilic PoorlyWater-Soluble Drugs: Spray-Dried Dispersions to Improve Oral Absorption and Enable High Dose Toxicology Studies of a P2Y1 Antagonist. J Pharm Sci. 103: 3924–3931 (2014).
 
4. Enabled oral delivery of poorly water soluble drugs through solubilized dosage forms: This research area focuses on the utility of solubilized formulation strategies (pH modulation, cosolvents, cyclodextrins, sub-micron emulsions, self-emulsifying drug delivery systems(SEDDS), lipids/phospholipids, liposomes), modification of the solid form of the drug (nanoparticles, amorphous drug solids, amorphous solid dispersions with polymers, salt selection, cocrystals, coprecipitates) or direct molecular modification through prodrugs and softdrugs. The specialized nature of these delivery systems often requires extended efforts to mitigate instability of the drug. These approaches are applied to both small molecule NCEs and peptide drugs for oral delivery.
 
a.  Morgen M, Gudmundsson O, Haskell R, Kumar A, Rao A, Su C, Goodwin A, Holenarsipur V, Cape J, Hageman M, Saxena A, Chowan GS, Chen X, Miller W, Nkansah R. Lipophilic Salts of Poorly Soluble Compounds to Enable High-Dose Lipidic SEDDS Formulations in Drug Discovery. Eur. J. Pharm. Biopharm. 117 (2017) 212-223.
b.  Chen XQ, Gudmundsson O, Hageman M. Application of Lipid-Based Formulations in Drug Discovery. J Med Chem. 55(18):7945-56 (2012).
c. Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, Kuo M, Hageman MJ. Development of a supersaturatable formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 92(12), 2386-2398 (2003).
d. Hovorka SW, Hageman MJ, Schöneich C. Oxidative Degradation of a Sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone in Aqueous/Organic Cosolvent Mixtures. Pharm Res. 19, 538-545 (2002).
 
5. Enabling the suceessful transition of drugs from discovery into development: Significant efforts have been employed to incorporate “developability” into the molecules that we design and select for clinical development. The end result is a mitigation of development risks and reduction in attrition of molecules during later phase development. We have actively developed stage-appropriate tools which can be used in discovery with minimal drug, limited time and on a higher
throughput basis. These tools are designed as surrogate measures to assess later phase development risk. The pharmaceutical properties resulting from molecular design include the deliverability of the molecule and a potential marriage of molecular properties to a given formulation strategy.

a.  Foster KA, Fancher RM, Proszynski M, Dixon G, Ford K, Cornelius G, Gudmundsson O, Hageman MJ. Utility of Gastric Retained Alginate Gels to Modulate PK Profiles in Rats. J Pharm Sci. 102(8):2440-9 (2013).
b.  Amidon GE, He X, Hageman MJ. Physicochemical characterization and oral dosage form selection based on the biopharmaceutics classification system. In: Vol. 3, Burger’s Medicinal Chemistry, Drug Discovery and Development, Seventh Edition. Abraham DJ, Rotella DP, eds.; John Wiley & Sons, Inc., October 2010.
c.  Hageman MJ. Preformulation Designed to Enable Discovery and Assess Developability. Combin Chem High Throughput Screening. 13(2):90-100 (2010).
d.  Guo J, Elzinga PA, Hageman MJ, Herron JN. Rapid throughput solubility screening method for BCS Class II Drugs in animal GI fluids and simulated human GI fluids using a 96-well format. J Pharm Sci. 97(4):1427-42 (2008).

Service

Positions
1985-1987 Scientist I, Pharmacy Research, Veterinary Biologics, Upjohn Co., Kalamazoo, MI
1987-1990 Scientist II, Drug Delivery R&D, Human and Veterinary, Upjohn Co., Kalamazoo, MI
1991-1996 Senior Research Scientist III, Solubilized Formulation Design, Upjohn Co., Kalamazoo, MI
1996-1999 Senior Scientist/Group Leader, Exploratory Formulations, Pharmacia & Upjohn, Kalamazoo, MI
1999-2003 Senior Fellow/Group Leader, Global Pharmaceutical Sciences Exploratory Formulations, Pharmacia Co., Kalamazoo, MI
2002-2004 Head Global Workstream for Cross-division Re-engineering of Biological Target Selection to First in Human Process, Pharmacia Co., Kalamazoo, MI
2003-2005 Sr. Res. Fellow/Group Leader, Exploratory Formulations, Pfizer Global R&D, Kalamazoo, MI
2004-2005 Chair of Michigan Cross-Divisional Pharmaceutical Sciences Technology Group, Pfizer Global R&D, Kalamazoo & Ann Arbor, MI
2005-2013 Group Director, Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ
2007-2010 Pharmaceutical Candidate Optimization Site Lead, Bristol-Myers Squibb, Princeton, NJ
2012-2016 Global Matrix Team Head, Biochemical & Biophysical Characterization
Network for Biologics, Bristol-Myers Squibb, Princeton, NJ
2013-2016 Executive Director, Pharmaceutical Candidate Optimization, Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ
2017-present Valentino J. Stella Distinguished Professor, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS

Selected Publications

Publications
Representative Publications can be found here.

Editorial Activities
Editor for the Journal of Pharmaceutical Sciences
(Editorial Board Here)
 
Prodrugs
Challenges and Rewards
Editors: Stella, V., Borchardt, R., Hageman, M., Oliyai, R., Maag, H., Tilley, J. (Eds.)
 
Optimizing the "Drug-Like" Properties of Leads in Drug Discovery
Editors: Borchardt, R., Kerns, E., Hageman, M., Thakker, D., Stevens, J. (Eds.)


 


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